Human papillomavirus type 16 E2 and E6 are RNA-binding proteins and inhibit in vitro splicing of pre-mRNAs with suboptimal splice sites

Bodaghi, Sohrab; Jia, Rong; Zheng, Zhi-Ming

doi:10.1016/j.virol.2008.12.037

Cited by 49 publications

(56 citation statements)

References 54 publications

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“…it has previously been demonstrated by Bell et al that hpV E4 protein interacts with SR-specific kinase SRPK1, which consequently impairs spliceosome assembly (27). In addition, Bodaghi et al showed that hpV16 proteins E2 and E6 are rna-binding proteins and may affect splicing both by binding directly to pre-mrna and by interacting with splicing factors (28). it was previously described that hpV proteins also regulate gene expression at the transcriptional level and affect splicing by the up-regulation of splicing factors.…”

Section: Discussionmentioning

confidence: 97%

IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions

Koczorowska

Kwaśniewska

Goździcka-Józefiak

2010

Experimental and Therapeutic Medicine

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Abstract. human papillomavirus (hpV) plays a crucial role in cervical cancer etiology. however, not all hpV-infected women develop cancer, indicating that additional cellular factors facilitate carcinogenesis. the aim of this study was to analyze the expression profile of insulin-like growth factor 1 (iGF1) isoforms in the context of FOx2, Sp1 and iGF1 receptor (iGF1r) expression during hpV-dependent cervical carcinogenesis. One hundred and nine epithelial tissue samples from women with pre-cancerous and cancer lesions of the cervix were analyzed. HPV DNA was identified by pcr, and real-time pcr was used to quantify the expression levels of the analyzed genes. all IGF1 mrna splicing isoforms were up-regulated in pre-cancerous cells, and a shift in the balance towards mitogenic iGF1Eb was observed in the cancer samples. IGF1 expression was controlled mainly by the p1 promoter, and an increase in p2 usage was observed in the cancer. correlations between IGF1 mrna splicing isoforms and the FOx2 splicing factor, as well as p1/p2 activity and Sp1 transcription factor expression levels were detected. no correlation was observed between the expression of iGF1 and its receptor iGF1r. Our results suggest that iGF1, in particular its splicing profile, may be an additional prognostic factor in cervical carcinogenesis.

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Section: Discussionmentioning

confidence: 97%

IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions

Koczorowska

Kwaśniewska

Goździcka-Józefiak

2010

Experimental and Therapeutic Medicine

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“…The hinge regions of the Betapapillomavirus E2 proteins are particularly rich in RS/SR dipeptides motifs, and they have been shown to mediate interactions between E2 and cellular SR proteins (60). Interestingly, the HPV16 E2 protein, whose hinge region does not contain RS dipeptide motifs, also associates with multiple SR proteins (61). The interaction with cellular splicing factors may contribute to E2-mediated posttranscriptional regulation of cellular and/or viral gene expression during the virus life cycle (60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the HPV16 E2 protein, whose hinge region does not contain RS dipeptide motifs, also associates with multiple SR proteins (61). The interaction with cellular splicing factors may contribute to E2-mediated posttranscriptional regulation of cellular and/or viral gene expression during the virus life cycle (60)(61)(62). However, in the case of HPV1 E2, we have been unable to identify interactions between SR proteins (HA-tagged forms of SRSF1 to -4 and SRSF7) and unphosphorylated or SRPK1 phosphorylated forms of the E2 protein (M.…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus Type 1 E1^E4 Protein Is a Potent Inhibitor of the Serine-Arginine (SR) Protein Kinase SRPK1 and Inhibits Phosphorylation of Host SR Proteins and of the Viral Transcription and Replication Regulator E2

Prescott

Brimacombe

Hartley

et al. 2014

J Virol

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The serine-arginine-specific protein kinase SRPK1 is a common binding partner of the E1^E4 protein of diverse human papillomavirus types. We show here for the first time that the interaction between HPV1 E1^E4 and SRPK1 leads to potent inhibition of SRPK1 phosphorylation of host serine-arginine (SR) proteins that have critical roles in mRNA metabolism, including pre-mRNA processing, mRNA export, and translation. Furthermore, we show that SRPK1 phosphorylates serine residues of SR/RS dipeptides in the hinge region of the HPV1 E2 protein in in vitro kinase assays and that HPV1 E1^E4 inhibits this phosphorylation. After mutation of the putative phosphoacceptor serine residues, the localization of the E2 protein was altered in primary human keratinocytes; with a significant increase in the cell population showing intense E2 staining of the nucleolus. A similar effect was observed following coexpression of E2 and E1^E4 that is competent for inhibition of SRPK1 activity, suggesting that the nuclear localization of E2 is sensitive to E1^E4-mediated SRPK1 inhibition. Collectively, these data suggest that E1^E4-mediated inhibition of SRPK1 could affect the functions of host SR proteins and those of the virus transcription/replication regulator E2. We speculate that the novel E4 function identified here is involved in the regulation of E2 and SR protein function in posttranscriptional processing of viral transcripts. IMPORTANCEThe HPV life cycle is tightly linked to the epithelial terminal differentiation program, with the virion-producing phase restricted to differentiating cells. While the most abundant HPV protein expressed in this phase is the E4 protein, we do not fully understand the role of this protein. Few E4 interaction partners have been identified, but we had previously shown that E4 proteins from diverse papillomaviruses interact with the serine-arginine-specific protein kinase SRPK1, a kinase important in the replication cycles of a diverse range of DNA and RNA viruses. We show that HPV1 E4 is a potent inhibitor of this host cell kinase. We show that E4 inhibits SRPK1 phosphorylation, not only of cellular SR proteins involved in regulating alternative splicing of RNA but also the viral transcription/replication regulator E2. Our findings reveal a potential E4 function in regulation of viral late gene expression through the inhibition of a host cell kinase. H uman papillomaviruses (HPVs) cause hyperproliferative warts and papillomas of the squamous epithelium at different body sites. Infection of the anogenital tract and oropharynx can lead to benign and malignant disease. There are 13 HPV types defined as causative agents of cancers at these sites, the most common being HPV 16 (HPV16) and HPV18. Of the viruses that infect cutaneous surfaces, some, such as HPV1, cause only benign warts, while infection with others, such as HPV5 and HPV8, can, in immunocompromised individuals, cause the formation of lesions that are at risk of malignant conversion.Despite the heterogeneity in pathogenesis, HPVs show a ...

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“…An early report indicated that the ␤-genotype HPV5 E2, which carries a long hinge region, could regulate both transcription and splicing of reporter pre-mRNAs (19). However, a later study could not verify this finding and instead found that the ␣-genotype HPV16 E2, which possesses a much shorter hinge region (14), could inhibit splicing in vitro (21). Although E2 does not possess an RNA recognition motif required by the SRSFs for RNA binding (11), one study showed that HPV16 E2 could bind RNA directly via its carboxy-terminal domain in a UV cross-linking assay (21).…”

Section: E2 As An Srsfmentioning

confidence: 99%

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Graham

2016

J Virol

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The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelium. This means that viral proteins must exert control over epithelial gene expression in order to optimize viral production. The HPV E2 protein controls replication, transcription, and viral genome partitioning during the viral infectious life cycle. It consists of a nucleic acid-binding domain and a protein-protein interaction domain separated by a flexible serine and arginine-rich hinge region. Over the last few years, mounting evidence has uncovered an important new role for E2 in viral and cellular RNA processing. This Gem discusses the role of E2 in controlling the epithelial cellular environment and how E2 might act to coordinate late events in the viral replication cycle. HUMAN PAPILLOMAVIRUS LIFE CYCLEH uman papillomaviruses (HPVs) are small (ϳ8.0-kbp) circular double-stranded DNA viruses that infect epithelial cells (keratinocytes) (1). There are more than 200 HPV genotypes. For the most part, HPVs of the ␣-genotype group infect mucosal epithelia, while the ␤-genotypes infect predominantly cutaneous epithelia (2). Most HPV infections are asymptomatic, or they manifest as benign lesions or warts. They are usually transient and are eventually cleared by the immune system (3). Despite this, HPVs cause a high burden of clinically significant disease worldwide, because the anogenital mucosa-infective high-risk group of HPVs (HR-HPVs) can cause persistent infection that leads to epithelial dysplasia and neoplasia. HR-HPVs are commonly associated with cervical cancer and tumors of other anogenital sites (2). Per annum, worldwide, there are around 500,000 new cases of cervical disease, and around 270,000 women die from cervical cancer. The two most prevalent HR-HPVs are HPV16 and -18, which are targeted by the current HPV vaccines (4). Over the last few decades, epidemic HR-HPV infection, especially in men, has been associated with a significant increase in oropharyngeal cancers (5). Certain cutaneous HPVs can also cause tumors (squamous cell carcinomas) in immunocompromised or immunosuppressed individuals (6). Thus, the causative association of HPV infection with a number of significant cancers indicates that increased understanding of the viral life cycle is essential.The HPV life cycle is intimately linked to epithelial differentiation (Fig. 1A) (2). HPV normally infects dividing cells at the base of the epithelium (basal layer) but completes its life cycle by amplifying progeny DNA genomes in the midepithelial layers (spinous layer) and carrying out viral encapsidation in the uppermost epithelial layer (granular layer) (Fig. 1A). Viral production is achieved through a highly orchestrated and complex viral gene expression program (Fig. 1A) (2). Mature virions are released upon shedding and disintegration of dead superficial epithelial cells into the environment. As a necessity, HPV infection alters the normal differentiation pattern of the epithelium and controls cellular gene expression to support viral re...

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Human papillomavirus type 16 E2 and E6 are RNA-binding proteins and inhibit in vitro splicing of pre-mRNAs with suboptimal splice sites

Cited by 49 publications

References 54 publications

IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions

IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions

Human Papillomavirus Type 1 E1^E4 Protein Is a Potent Inhibitor of the Serine-Arginine (SR) Protein Kinase SRPK1 and Inhibits Phosphorylation of Host SR Proteins and of the Viral Transcription and Replication Regulator E2

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

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